4R-amino-1t-phenyl-1c-ethoxycarbonyl-cyclohexenes-(2) and process for their preparation

ABSTRACT

wherein R1 and R2 are the same or different and are hydrogen or alkyl having 1 to 4 carbon atoms, or one of the two groups is allyl, phenalkyl having 7 to 9 carbon atoms or Alpha -methylBeta -hydroxyethyl; or R1 and R2 together form a morpholino group, piperazino group substituted at the 4-position by methyl, benzyl, phenyl, 3-chlorophenyl, 4-chlorophenyl, 2-phenethyl or benzoyl, or a piperidino group substituted at the 4-position by hydroxyl, phenyl, 2-methoxyphenyl, 4-methoxyphenyl, methyl or benzyl and medically acceptable addition compounds derived from inorganic and organic acids or lower alkyl halides. The compounds of the present invention are prepared by separation of 4-amino-1phenyl-1-ethoxycarbonyl-cyclohexenes-(2), described in U.S. Pat. application Ser. No. 226,509, filed Feb. 15, 1972, into the two possible geometrical isomers. The instant compounds, the 4ramino-1t-phenyl-1c-ethoxycarbonyl-cyclohexenes-(2) of formula I, exhibit marked analgesic and neuroleptic activities and are useful for the alleviation and reduction of pain.   This invention relates to 4r-amino-1t-phenyl-1c-ethoxycarbonylcyclohexenes-(2) of formula I:

United States Patent 1191 Satzinger et al.

1 51 Sept. 16, 1975 [-75] Inventors: Gerhard Satzinger, Denzlingen;

Manfred Herrmann, Gundelfingen, both of Germany [73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: July 27, 1973 [21] App]. No.1 383,421

Related U.S. Application Data [63] Continuation-impart of Scr. No. 226.509 Feb. 15.

[58] Field of Search... 260/268 R, 247.2 B, 293.81, 260/47l A 268 PH [56] References Cited UNITED STATES PATENTS 3,557,127 1 1971 Satzinger 260/293.81

Primary E.\'aminerDonald G. Daus Assistant E.\'aminer.lose Tovar Attorney, Agent, or Firn1-Albert H. Graddis; Frank S. Chow; George M. Yahwak [57] ABSTRACT This invention relates to 4r-amino-lt-phenyl-lcethoxycarbonyl-cyclohexenes-(2) of formula I:

wherein R and R are the same or different and are hydrogen or alkyl having I to 4 carbon atoms. or one of the two groups is allyl. phenalkyl having 7 to 9 carbon atoms or oz-methyl-B-hydroxyethyl; or R and R together form a morpholino group. piperazino group substituted at the 4-position by methyl. benzyl, phenyl. 3-ehlorophenyl, 4-chlorophenyl. Z-phenethyl or benzoyl, or a piperidino group substituted at the 4- position by hydroxyl. phenyl. Z-methoxyphenyl. 4- methoxyphenyl, methyl or benzyl and medically acceptable addition compounds derived from inorganic and organic acids or lower alkyl halides. The compounds of the present invention are prepared by separation of 4-amino-1-phenyll-ethoxyearbonyleyclohexenes-(Z). described in U.S. Pat. application Ser. NO. 226.509, filed Feb. 15, 1972. mm the two possible geometrical isomers. The instant compounds the 4r-aminolt-phenyl l e-ethoxycarbonyL eyclohexenes-(2) of formula I. exhibit marked analgesic and neuroleptic activities and are useful for the alleviation and reduction of pain.

6 Claims, No Drawings 4R-AM1NO- lT-PHENYL- l C-ETHOXYCARBONYL- CYCLOHEXENES-(2) AND PROCESS FOR THEIR PREPARATION This application is a continuation-in-part of our copending application, U.S. Ser. No. 15, 1972.

BRIEF DESCRIPTION OF THE INVENTION The compounds of formula I, in which the l-phenyl substitutent is trans to the 4-amino group, are obtained by fractional crystallization of compoundsof formula II into its geometrical components, compounds of formula l and compounds of formula Ill. The l-phenyl substituent is cis to the 4-amino group in compounds of formula III. The separation of the mixture of geometrical isomers into compounds of formulas l and III is also achieved by fractional crystallization of the salts and quaternary ammonium compounds corresponding to bases of formula ll. The 4r-aminolt-phenyl isomers of formula I are secured by thermolysis of the separated quaternary ammonium compounds of formula V. The synthesis of the amino esters depicted by formula II is described in our copending US. Pat. application Ser. No. 226.509. filed Feb. 15, I972.

in formulas l to Vl. R and R denote hydrogen. alkyl having 1 to 4 carbon atoms. allyl. phenalkyl having 7 to 9 carbon atoms or oz-methyl-B-hydroxyethyl; R and R together for a morpholino group. a piperazino group substituted at the 4-position by methyl. benxyl. phenyl. 3-chlorophenyl. 4-chlorophenyl. lphenethyl or benzoyl, or a piperidino group substituted at the 4-position by hydroxyl. phenyl. Z-methoxyphenyl; 4- methoxyphenyl, methyl or benzyl'. R is alkyl having 1 to 4 carbon atoms and X is an anion such as halide. methylsulfate or the like.

The aminoesters of formula I are converted to medically acceptable addition compounds derived from organic and inorganic acids or lower alkyl halides having 1 to 4 carbon atoms.

The aminoesters of formula I possess beneficial analgesic and neurolcptic properties as determined by the phenyl-p-quinone writhing test and the photoeage. body temperature-reduction and aggression tests. respectively. The compounds of formula l are useful for the alleviation and reduction of pain.

DETAILED DESCRlPTlON OF THE INVENTION The synthesis and pharmacological properties of 4- aminol -phenyll -ethoxycarbonyl-eyclohexenes-( 2) of formula ll are disclosed in our copending US. Pat. application Ser. No. 226.509. filed Feb. l5. 1972. The synthetic process described in the aforementioned application yields mixtures of amino esters of formula ll. that is. amino esters in which the l-phenyl group is cis or trans to the amino group attached to the 4-position of the cyclohexene ring. The amino esters so described exhibit analgesic and neurolcptic activity. a new and useful combination of pharmacological effects associated with a given chemical composition.

The present invention relates to -lr-amino-ltpheny'llc-ethoxycarbonyl-cyclohexenes(2) of formula I wherein R and R are hydrogen, alkyl having 1 to 4 carbon atoms. allyl. phenalkyl having 7 to 9 carbon atoms or (t-methy'l-B-hy'droxyethyl or R, and R together form a morpholino group. a piperaxino group substituted at the 4-position by methyl. benzyl. phenyl. 3-chlorophenyl. 4-chlorophenyl. Z-phenethyl or ben- 7.oyl or a piperidino group substituted at the 4-position by hydroxyl. phenyl. Z-methoxyphenyl. 4- methoxyphenyl. methyl or benlyl and medically ac ceptable addition compounds with inorganic and organic acids or lower alkyl halides of l to 4 carbon atoms.

The aminoesters depicted by stereostructure l are obtained by fractional crystallization of the aminoesters portrayed by structure ll from a suitable solvent such as acetone. ethyl acetate. methanol. Z-propanol or benzene or mixtures thereof. followed by recrystallization of the stereo pure base of formula I from an aromatic hydrocarbon such as benzene or toluene. Salts. preferably hydrochlorides. of mixtures of isomeric aminoesters of formula II. prepared by treatment of said aminoesters with an inorganic acid. preferably hydrogen chloride. are also separated by fractional crystallization from the aforementioned solvent systems. Alternatively. quaternary ammonium compounds of formula IV. preferably methiodides. synthesized by treatment of the aminoesters of formula II with alkylating agents having l to 4 carbon atoms in the alkyl residue. preferably methyliodide are separated into the lt-phenyland lcphenyl-quaternary ammonium compounds of formulas V and VI. The resolved ammonium compounds of formulas V and VI are converted into the corresponding ammonium acetates by exchange with an iong exchange resin such as Amberlite lRA 400 (acetate form). The quaternary ammonium acetates of formulas V and Vl wherein Xis acetate are thermally monodemcthylated to the stereoisomeric amines of formula l and Ill. The thermal demethylation of the aforementioned acetates is performed at the boiling point of a solvent system composed of about 1 part by volume of acetonitrile to 3 parts by volume of toluene.

The aminoesters of formula I are transformed to salts. preferably hydrohalides, by dissolution of the base in a suitable solvent such as e ther or Z-propanol followed by treatment of the solution with a hydrogen halide. For example. hydrochlorides of the amino esters of formula I are obtained when an ether or 2- propanol solution of compounds of formula I are treated with hydrogen chloride.

in the nomenclature of the compounds described in this invention. the lower case letters 1'. c. and I mean reference radical. cis and trans. respectively. and refer to the relative geometry of the functional groups. the amino. ethoxycarbonyl and phenyl groups. with respect to the cyclohexene ring system. For example. in the name of the compound. 4r-amino-lt-pheny'l-lcethoxycarbonyl-eyclohexene-( 2 the letter r preceding the term "amino" signifies that the amino group was arbitrarily chosen as the reference radical and in this case occupies the position above the average plane of the cy'clohexene ring. The letter 0 preceding the term "ethoxycarlmnyl denotes that the ethoxycarbonyl group is cis to the reference radical. that is. is located on the same side of the average plane of the cyclohexene ring as the amino group. The letter 1 preceding the term phenyl" means that the phenyl group is trans to the reference radical. that is. is situated on the opposite side of the average plane of the cyclohexene ring as the amino group. A solid line drawn from the cyclohexene ring to a substituent means that the group is situated above the average plane ofthe cyclohexene ring. a broken line means that the group is located below the plane.

The compounds of the present invention. 4r-aminol t-phenyl l c-ethoxycarbonyl-cyclohexenes-( Z of for mula l. exhibit both analgesic and neurolcptic activity as shown by the data presented in the following chart:

Aggressive Substance Acute Toxicity Analgesia Reduction of Decrease in (Hydrochloride) LD 50 lil) 5U lug/kg Spontaneous Body Mouse rug/kg Phcnyl-p-Quinone Motility by '1 Temperature El) 50 mg/kg (Mouse) \Nritliing Test Photocage in Y (Mouse) lithy'l l'mcthyl s.c. I54 s.c. (1.3 lit rug/kg s.c. s.e. no effect 15 mur'ke s.c. J-plienyl-piper Lg. I52 i.g 2N5 30" Lg no effect ig. no iffect idin-J-earboxy late ll)olitnti|1) -Continucd Substance Acute Toxicity Analgesia Reduction of Decrease in Aggressive (Hydrochloride) LD 50 ED 50 mg/kg Spontaneous Body Mouse mg/kg Phenyl-p-Quinone Motility by Temperature ED 50 mg/kg (Mouse) writhing Test Photocage in C (Mouse) Lg. no effect (:l-3r-Dimethyls.c. 490 s.c. 15.9 s.c. no effect so no effect s.c. no effect amino-4c-phenyl Lg 437 Lg. 14.0 Lg. no effect Lg. no effect Lg. no effect 4t-ethoxyearbonylcyclohcxenc-( l (Valoron") 4rDimethyls.e. l55 s.c. 3.0 5.0 mg/kg s.c. mg/kg s.c. 4.0 mg/kg s.c. amino-lt phenyl- Lg. 297 Lg. I16 38)? "L-l" lc-cthoxy- 10.0 ing/kg s.c. carhonyl- 8271 cyclohcxenc( 2) (Example 1 4r-(4-Phenyl- Lg. 800 Lg. l0.0 ing/kg Lg. 50 ing/kg Lg. mg/kg Lg. pipcridino-l A -0.5 lt-phenyllcethoxycarbonyb cycloheXene-( 2) (Example 3) 4r-(4-Phenyl- Lg 850 Lg. I00 mg/kg Lg. Lg. no effect Lg no effect piperidino-l ca. 75.0 79% lc-phenyll t ethoxycarbonylcyclohexenc-( 2) 4r (4'-Phenyl- Lg. 1600 Lg 25.0 5.0 mg/kg s.c. 100 mg/kg Lg 25 mg/kg Lg, piperazinod 7=l'/r [0.0 mg/kg -16 lt-phenyl-lc- Lg. 59%. ethoxycarbonylmg/kg Lg. cyclohcxene-( 2) 94% (Example 5) v 4r-Dimethyls.c. I36 s.c. 14.6 5.0 mg/kg s.c. so no effect' s.c. no elTect amino'lc-phenyl- Lg. 490 Lg. l l8.0 ()Z ll-ethoxy- 20.0 mg/kg s.c. carbonyl- 25'! cyclohexenc-( 2) 4r-(Piperidinos.c. I50 s c. 53 I00 ing/kg s.c. 25 ing/kg s.c. 8.0 mg/kg s.c. l l t-phcnyl- 93); -l .o le-cthoxycarbonyl- Cyelohcxene-( 2) (Example 2) 4r-( Piperidinos.c. 390 s.c.)20.0 40.0 mg/kg s.c. 50 mg/kg s.c. s.e. no effect l')- lc-phcnyll 1'1 4L1 lt-ethoxy- Carbonyl' cyclohexene-( 2) 4r-(4'-Phcnyl- Lg. ca. Lg 500 5.0 mg/kg s.c. 200 mg/kg Lg. pipcrazinol I600 no effect l .7 lc-phenyl-ltl0 mg/kg Lg. cthoxycarhonyl- 34C? cyclohexene-( 2) 4r-[4(2-Mcthoxy- Lg. ca. Lg. 50.0 50 mg/kg Lg. 200 mg/kg Lg. no results phe|1yl)pipcra'/.ino- 2000 8(14 so far l'l-lt-phenyl-lcethoxycarbonylcyclohexene(2) (Example 4) 4r-l4'-(2-Methoxyi.g. I600 i.g. l50.00 50 mg/kg Lg.

phenyl )piperazinol l c phenyl-ltcthoxycarbonylcyclohcxene-( 2) The lethal dose (l.D)-50 values were determined in mice by acute toxicity measurements. Analgesic activity was ascertained in mice utilizing the phenyl-pquinone writhing test and the results are presented in effective dose (ED)-50 values. Neuroleptic activity was determined in three pharmacological tests; the photocage, the body temperature reduction and aggressive mouse tests. The results are given in the dose required to obtain the indicated effect for the photocage and body temperature reduction tests and in effective dose 50 values for the aggressive mouse test. The test compounds were administered subcutaneously (s.c.) and intragastrically (Lg.

The methodology employed for the determination of the acute toxicity values and analgesic and ncuroleptic activity (by the photocage and body temperature reduction tests) is described in German Patent Applica tion No. P II 07 87 l .742 and is presented in Example 6. 8 and 9. respectively. ofthis application. In addition to the photocage and body temperature reduction tests. the aggressive mouse test was utilized to further define the neuroleptic (major tranquiliriation) activity of the compounds included in the chart.

When male mice are isolated in cages. some of the animals dcvelope the habit of furiously defending their territory against intruders ofthe same sex. Experiments which influence this aggression can be used for the testing of inhibitory acting psychotropic drugs. The aggressive behavior can be influenced lby neurolcptics (major tranquilizers) and tranquilizers (minor tranquilizers). Neuroleptics suppress the aggressive behavior at doses which do not influence motor activity and minor tranquilizers" are effective only at high doses. which often produce ataxia.

Test animals were male mice (NMRI) which were isolated in Makrolon cages for at least 5 weeks. After which had not become aggressive or which showed no reaction within one minute were not used in the main l test performed two days after the preliminary testfOn" the test day the mice. fasted and isolated for 16 hours. were administered the test substance and the aggressive behavior towards a partner of the same sex was studied.

after 30 minutes. As in the preliminary test. the criterion was aggressive behavior within one minute. Each test group consisted of 6 animals. Animals which did not show aggressive behavior within one minute were regarded as protected. The lid-50 values were determined. The 4r-aminolt-phenyl- 1 c-ethoxycarbonyleyclohexenes-(Z) of formula 1. the compounds of this invention. are effective analgesics when administered orally to mammals such as mice and rats at a dose level of about 5 to 75 mg/kg of body weight. more particularly at a dosage of about to 50 mg/kg of body weight. The dosage regimen may be different in other mammalian species depending upon factors wellknown to those skilled in the medical arts.

The compounds of formula I can be formulated into various dosage forms for oral. parenteral or rectal administration. lncluded in these dosage forms are tablets. capsules. suspensions. emulsions. syrups. supposi tories and other liquid and solid compositions known to those skilled in thepharmaceutical arts. Among the inert excipients formulated with the analgesicneurolcptic compounds of formula 1 are gelatin. lactose. starches. water. oils. gums. polyalkylcne glycols. petroleum jelly and other compatible adjuvants routinely used for the preparation of medicaments. In addition. preservatives. stabilizers. buffers. \vetting agents. etc. may be included in the formulations. Theaforementioned dosage forms are prepared by convem tional methods and techniques.

The compounds of formula 1. in which the -1amino and l-phenyl substituents are locatcd'on opposite sides of the average plane 'of thc cyclohexene ring. exhibit both analgesic and neuroleptic activity. a desirable and beneficial combination of biological effects for the treatment of conditions involving acute pain. At pres ent. combinations of analgesics and neuroleptics such as phenothiayincs are used to both alleviate pain and calm the subject. that is. to achieve the same overall beneficial effect as obtained with the compounds of this invention. compounds of formula 1. The combina tion of analgesic und neuroleptic activities associated with asingle chemical entity is notonly unknown in'the prior art but isalso an unexpected result. An equally uncxpected'result is the experimental observation that The following examples serve to illustrate the embodiment ofthe invention and are not to be construed as limiting the scope of the invention.

EXAMPLE 1 4r-Dimethylaminol t-phenyll c-ethoxycarbonyleyclohexene-( 2) 273 g of 4-Dimethylamino- 1 -phenyll-ethoxycarbonyl-cyclohexene-(Z) (isomeric ratio lt-phenyl/lcphenyl 3/7 according to (PC-analysis) dissolved in 3 L of benzene, are mixed with 142 g of methyl iodide and stored at 20C for 24 hours. The crystalline mixture of the methiodides (yield 400 g) is collected and fractionally recrystallized from acetone. 120 g of pure 4r-dimethylaminol t-phenyll c-ethoxycarbonylcycloheXene-( 2) methiodide. mp. 175C. are obtained as the more soluble component. The substance is dissolved in 2.4 L of methanol; the solution is run through a column filled with amberlite 1RA 400 in the acetate form. The residue of the methanolic eluant is freed from traces of water by azeotropic destillation with toluene and is then taken up in a mixture of 2.25 L of acetonitrile and 6.7 L of toluene. The solution is heated under reflusfor 16 hours. After removal of the solvent. the residue is dissolved in fresh-toluene. washed with a small volume of KHCO -,-solution and then with water.

the comespondinggeometric isomers of compounds of formuli -(2) t tf.ttbrmula lll ..in which the -1-amino and l -p.cn J tent analgesic. than compounds of formula l-but are essentiallydevoid ofi eur oleptic activity.

Several of the eon ipounds of formula I. particularly 4r-dimethylaii ino 1t-phenyl;l e-ethoxycarbonylcyclohexene 2 are more potent analgesics-than (i)- 3r-diniethylamino-4cphenyl-4t-ethoxycarbonyleyclohexene-( 1 (Valoron). a positional isomer of the. former and Dolantin. the dominant analgesic for acute ,1. -lr-aminolc -phenyl- 1 t-ethoxycarbonylubstituents are cis. are not. only less po-- pain. Valoron and Dolantin possess no filglllfltjillll llkillr roleptic"acti\ ii Cale: C 65.8) H 7.81 (l 11.45 N 4.52 Found: C 65.98 H 7.86 C1 11.74 N 4.80

EXAMPLE 2' 4r-( Piperidino-l l t-phenyllcethoxycarbonylcyclohexene-( 21 31.3 of 4-Piperidino-1-phenyl-l-ethoxycarbonylc vclohexene-( 2) (isomeric ratio lt-phenyl/lc phenyl 6.5/3.5 according to (EC analysis) are dissolved in 500 cc ofether and transformed into the'crystalline mixture of the isomeric hydrochlorides (yield 34.0 g) by means of HCl-gas dissolved in ethyl acetate. The less soluble hydrochloride of the lt-phenyl-compound is obtained in 96); purity by fractional crystallization from isopropanol/methanol 19:1.) and in 999; purity (GC- determination) by subsequent recrystallization from isopropanol free from methanol. Yield 9.1- g. m.p. 221 -223C. QuH ttlm 349.9

(alcg 68.65 H 8.06 (l 10.13 N 4.00 Found: C 68.76. H 8.04 (1 10.27 N 4.18

.liXAMPLli 3 transformed into the 'hydrochloride'as in Example 2.

The less soluble lt-phenyl-isomer is obtained TLC pure by fractional cr stalli ation from isopropanol and subsequent recrystallivation from toluene. Yicld 12.0 g. m p. 238 -240 0 (nrp of the pure trans-isomer C 73.62 H 7.52 Cl 8.06 N 3.48

mix-mp. C N CINO EXAMPLE 4 4r-[4'-( 2- Methoxyphenyl )piperazinol l t-phenyllc-ethoxycarbonyl-cyclohexene-( 2) 42.1 g of 4-[4'-(2-Methoxyphenyl)piperazino-l ]-lphenyll -ethoxycarbonyl-cyclohexene-( 2) (isomeric ratio according to TLC lt-phenyl/lc-phenyl 7/3). dissolved in ether, are transformed into the hydrochloride as in Example 2. The isomers are separated by fractional crystallization from benzene. The sparingly soluble lt-phenylisomer is obtained in pure form by subsequent recrystallization from toluene. Yield 12.3 g, m.p. 182-1 83C. C H CIN O (457.03)

Cale: C 68.33 H 7.28 Cl 7.76 N 6.l3 Found: C 68.21 H 7.40 Cl 7.80 N 6.28

EXAMPLE 5 4r-( 4'-Phenylpiperazinol l t-phenyl- I cethoxycarbonyl-cyclohexene-(2) 39 g of 4-(4-Phenylpiperazino-l )-l-phenyl-lethoxycarbonyl-cyclohexene-( 2) (isomerism according to TLC ltphenyl/lc-phenyl 3:2) are fractional]; crystallized from ethanol (96%). 20 g of lt-phenylisomer. obtained in 8071 purity. are obtained in pure form by recrystallization from methanol or n-hexane. Yield g. m.p. 95-96C. The hydrochloride is pre cipitated from isopropanol by means of HCl-gas. M.P. 207208C. C .-,H;, ClN. ,O (426.9)

Cale: C 70.33 H 7.32 Cl 8.30 N 6.56 Found: C 70.16 H 7.33 CI 8.94 N 6.53

EXAMPLE 6 Acute Toxicity Test animals were male mice (NMRI) weighing 18 to 23 g. The animals were fasted for 24 hours prior to the beginning of the test. water being available ad libitum. Each dose was tested in 6 animals. and was increased by a factor 1.5 to 2.0. The volume of liquid administered amounted to 2 ml in intragastric application and l ml/l00 g of body weight in subcutaneous application. The observation time was 48 hours.

EXAMPLE 7 PhenyLp-quinone Test Each dose was administered to 12 male mice weighing l8 to 23 g. Phenyl-p-quinone, 1.25 ml of a 0.02% solution per 100 g of body weight, was administered intraperitoneally 15 minutes after application of the substances to be investigated. Animals which did not show a typical pain reaction during the following minutes were considered protected. The test was rejected if less than 10 out of 12 animals of the control group showed a reaction.

EXAMPLE 8 Photocage Test Test animals were male white mice weighing 18 to 23 g. Spontaneous motility was measured in a glass cage (25 X 50 cm.) through the transverse of which three infrared rays pass equidistantly. The number of interruptions of the infrared rays within 30 minutes was consid ered to express spontaneous motility. Each test group comprised 5 animals. The substances were applied either intragastrically with a stomach tube or subcutaneously.

EXAMPLE 9 Temperature-reducing Effect Test animals were male rate (SIV) weighing tc g. The body temperature was determined within the framework of a behaviour test according to lrwin in which 5 rats were treated with the test substances after observation of normal behaviour and determination of the normal temperature. After 30. 60 and 12(1 minutes the rats were again subjected to the specific test program. The values shown in the chart represent the difference between the initial body temperature and the temperature taken 2 hours following administration of the substance. The body temperature was taken rectally with a thermometer made by the Ellal. Company.

We claim:

1. A compound of formula I:

wherein R and R are alkyls having 1 to 4 carbon atoms or R or R together with the nitrogen atom form 4-phcnyl piperazino. 4-( 2-methoxy-phenyl) piperazino. piperidino, or 4-phcnyl piperidlino or pharmaceutically acceptable acid addition salts.

2. A compound according to claim 1 which is 4rdimethylaminol t-phenyll c-ethox \'carbonylcyclohexene-(Z).

3. A compound according to claim 1 which is 4r- (piperidino-l l t-phenyll c-cthox \'carbonylcyclohexene( 2).

4. A compound according to claim 1 which is 4r-(4'- phenylpiperidino-l l t-phcnyll c-ethoxycarbonylcyclohexene-( 2 5. A compound according to claim 1 which is 4r-( 4'- phenylpiperazino-l lt-phenyll c-ethoxycarlwnylcycloheXenc-( 2).

6. A compound according to claim 1 which is 4r-[ 4'- (2-methoxyphenyl )piperazinol l t-phenyll cethoxycarbonyl-cyclohexene-( 2 

1. A COMPOUND OF FORMULA 1:
 2. A compound according to claim 1 which is 4r-dimethylamino-1t-phenyl-1c-ethoxycarbonyl-cyclohexene-(2).
 3. A compound according to claim 1 which is 4r-(piperidino-1'')-1t-phEnyl-1c-ethoxycarbonyl-cyclohexene-(2).
 4. A compound according to claim 1 which is 4r-(4''-phenylpiperidino-1'')-1t-phenyl-1c-ethoxycarbonyl-cyclohexene-(2).
 5. A compound according to claim 1 which is 4r-(4''-phenylpiperazino-1'')-1t-phenyl-1c-ethoxycarbonyl-cyclohexene-(2).
 6. A compound according to claim 1 which is 4r-(4''-(2-methoxyphenyl)piperazino-1'')-1t-phenyl-1c-ethoxycarbonyl -cyclohexene-(2). 